Dataset Information

Molecular Characterization Reveals Subclasses of 1q Gain in Intermediate Risk Wilms Tumors.

ABSTRACT: Chromosomal alterations have recurrently been identified in Wilms tumors (WTs) and some are associated with poor prognosis. Gain of 1q (1q+) is of special interest given its high prevalence and is currently actively studied for its prognostic value. However, the underlying mutational mechanisms and functional effects remain unknown. In a national unbiased cohort of 30 primary WTs, we integrated somatic SNVs, CNs and SVs with expression data and distinguished four clusters characterized by affected biological processes: muscle differentiation, immune system, kidney development and proliferation. Combined genome-wide CN and SV profiles showed that tumors profoundly differ in both their types of 1q+ and genomic stability and can be grouped into WTs with co-occurring 1p-/1q+, multiple chromosomal gains or CN neutral tumors. We identified 1q+ in eight tumors that differ in mutational mechanisms, subsequent rearrangements and genomic contexts. Moreover, 1q+ tumors were present in all four expression clusters reflecting activation of various biological processes, and individual tumors overexpress different genes on 1q. In conclusion, by integrating CNs, SVs and gene expression, we identified subgroups of 1q+ tumors reflecting differences in the functional effect of 1q gain, indicating that expression data is likely needed for further risk stratification of 1q+ WTs.

SUBMITTER: van Belzen IAEM

PROVIDER: S-EPMC9564324 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Molecular Characterization Reveals Subclasses of 1q Gain in Intermediate Risk Wilms Tumors.

van Belzen Ianthe A E M IAEM van Tuil Marc M Badloe Shashi S Strengman Eric E Janse Alex A Verwiel Eugène T P ETP van der Leest Douwe F M DFM de Vos Sam S Baker-Hernandez John J Groenendijk Alissa A de Krijger Ronald R Kerstens Hindrik H D HHD Drost Jarno J van den Heuvel-Eibrink Marry M MM Tops Bastiaan B J BBJ Holstege Frank C P FCP Kemmeren Patrick P Hehir-Kwa Jayne Y JY

Cancers 20221005 19

Chromosomal alterations have recurrently been identified in Wilms tumors (WTs) and some are associated with poor prognosis. Gain of 1q (1q+) is of special interest given its high prevalence and is currently actively studied for its prognostic value. However, the underlying mutational mechanisms and functional effects remain unknown. In a national unbiased cohort of 30 primary WTs, we integrated somatic SNVs, CNs and SVs with expression data and distinguished four clusters characterized by affect ...[more]

PMID: 36230794

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Project description:1q gain/amplification (1q+) is the most common cytogenetic abnormality (CA), with a frequency of 30-50% in patients with newly diagnosed multiple myeloma (NDMM). Although accumulating evidence supports 1q+ as a "high-risk" CA (HRCA), several issues remain to be addressed to understand its true prognostic property. We retrospectively analyzed a cohort of 934 patients with NDMM from three centers in China, who had baseline data available for 1q+ [including 1q21 gain (3 copies) and amplification (> 3 copies)] detected by fluorescence in situ hybridization in isolated CD138+ cells, and who received first-line treatment with novel agents including proteasome inhibitors, immunomodulatory drugs, or both. Minimal residue disease (MRD) was assessed using next-generation flow cytometry. In this cohort, 1q+ patients accounted for 53% of all patients. 1q+ patients were characterized by larger tumor burden, more advanced diseases, adverse complications, and frequent concurrence of other CAs (particularly HRCAs) at diagnosis. Concurrence of HRCAs [del(17p), t(4;14), and t(14;16); known as double-hit MM], but not standard-risk CA, markedly worsened the outcome of 1q+ patients, compared to those with 1q+ only (progression-free survival/PFS: hazard ratio/HR 1.63, 95% confidence interval/CI 1.21-2.20, P = 0.0013; overall survival/OS: HR 1.96, 95% CI 1.40-2.74, P < 0.0001). 1q+ modulated the risk levels defined by the Revised International Staging System (R-ISS). Although the overall response rate was not significantly different between patients with or without 1q+, fewer 1q+ patients achieved complete response or better and minimal residue disease negativity (MRD-). MRD- attainment substantially prolonged PFS (HR 4.03, 95% CI 2.59-6.29, P < 0.0001) and OS (HR 3.72, 95% CI 2.24-6.19, P < 0.0001) of 1q+ patients. While 1q+ patients had relatively shorter MRD- duration, sustained MRD- significantly improved the PFS and OS of 1q+ patients. Together, 1q+ is an HRCA and a major component of double-hit MM, while the risk-adapted and MRD-tailored therapy may best help manage this high-risk population.

Dataset Information

Molecular Characterization Reveals Subclasses of 1q Gain in Intermediate Risk Wilms Tumors.

Publications

Molecular Characterization Reveals Subclasses of 1q Gain in Intermediate Risk Wilms Tumors.

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